ES2313897T3 - MASK OF THE FLAVOR OF ORAL CHINOLOGY LIQUID PREPARATIONS USING ION EXCHANGE RESINS. - Google Patents

Abstract

An aqueous pharmaceutical composition comprising: (a) from 0.1% to 10% by weight of a quinolone compound; wherein the quinolone compound is selected from orbifloxacin, grepafloxacin, nalidixic acid, sparfloxacin and trovafloxacin mesylate; (b) 0.2% to 20% by weight of a cationic ion exchange resin prepared from a porous copolymer of methacrylic acid crosslinked with divinylbenzene; and (c) pharmaceutically acceptable excipients to equal 100%.

Description

Masking the flavor of preparations oral quinolone fluids using exchange resins ionic.

Background of the invention 1. Field of the invention

The present invention relates to the formulation of oral liquid quinolone preparations or derivatives thereof, selected from orbifloxacin, grepafloxacin, nalidixic acid, sparfloxacin and mesylate trovafloxacin, using selected ion exchange resins of a cationic ion exchange resin prepared from a porous copolymer of methacrylic acid crosslinked with divinylbenzene; and a polystyrene ion exchange resin sodium sulfonate, as the support. The formation of a complex of quinolone-resin (resin) removes the end bitterness of quinolones to prepare the dosage form Tasty liquid oral.

2. Description of the related technique

Quinolone antibiotics are widely used in The treatment of common infections. Quinolone products current in the market, including orbifloxacin and ciprofloxacin, They are administered as tablets or capsules. Since the quinolones have an extremely bitter taste, has always a challenge is the development of oral dosage forms Tasty liquids They are useful oral oral dosage forms for patients who have difficulty swallowing capsules or tablets The Journal of Pharm. Sciences, vol 60, No. 10, p. 1523-1527 (October 1971) describes resins of ion exchange of polycarboxylic acid as adsorbates for mask the bad taste of ephedrine, dextromethorphan, pseudoephedrine and metapyrilene; EPO document 225615, published June 16, 1987, describes pharmaceutical compositions liquids containing dextromethorphan, exchange resin ionic (preferably a cationic resin) and vehicles Acceptable pharmacists, sweeteners and formulation aids. The taste is not a problem. US 4,808,411 issued on February 28, 1989, describes polymer compositions of antibiotic containing acrylic acid polymers and erythromycin. Such compositions can be prepared as liquids and they are effective in masking the taste of the antibiotic erythromycin; US 5,152,986, issued October 6, 1992, describes pharmaceutical compositions containing derivatives of quinolone carboxylic acid (such as ciprofloxacin) and ion exchange resins (preferably cationic) that they mask the bad taste of quinolone in animal feed. These compositions are in solid form and concentrate form; he EPO document 622083, published on November 11, 1994, describes a solid pharmaceutical preparation containing any number of therapeutic agents, such as antibiotics β-lactams, antihistamines, bronchodilators and anti-inflammatories, and exchange resins cationic or anionic ionic that decrease taste and smell unpleasant therapeutic agent.

There is still a need in the art of oral liquid quinolone preparations with an acceptable flavor. Applicants have satisfied this need in the art by preparing liquid quinolone preparations with An acceptable taste.

Definitions and uses of terms

The expression "pharmaceutical composition", as used in this document, means a composite combination for a safe and effective amount of the active compound ingredient of quinolone, or mixtures thereof, and pharmaceutically excipients acceptable.

The expression "pharmaceutically excipients acceptable ", as used herein, refers to any pharmacologically inactive and physiologically material inert known to a specialist in the art, which is compatible with the physical and chemical characteristics of active ingredient of particular quinolone compound that is select to use. The pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, emollients, disintegrants, solvents, cosolvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, dyes for pharmaceutical use or pigments and agents viscosity.

The expression "exchange resin ionic ", as used herein, refers to resins of anionic or cationic ion exchange.

The expression "oral dosage form", as used herein, refers to any composition pharmaceutical intended to be administered systemically to a individual by administration of said composition to the tract gastrointestinal of an individual, through the mouth of said individual. Oral dosage forms include tablets, coated or uncoated; liquids, such as solutions and suspensions; or capsules, coated or uncoated.

All percentages are based on percentage by weight unless otherwise indicated.

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Brief summary of the invention

The present invention relates to a aqueous pharmaceutical composition comprising:

(a) from 0.1% to 10% by weight of a compound of quinolone; wherein the quinolone compound is selected from orbifloxacin, grepafloxacin, nalidixic acid, sparfloxacin and trovafloxacin mesylate;

(b) from 0.2% to 20% by weight of a resin of cationic ion exchange prepared from a copolymer porous methacrylic acid crosslinked with divinylbenzene; Y

(c) pharmaceutically acceptable excipients to match 100%.

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The present invention further relates to a aqueous pharmaceutical composition consisting of

purified water at 33.75% (w / v);

2% orbifloxacin (w / v);

lactic acid at pH 4.5;

polystyrene ion exchange resin 12% (w / v) sodium sulfonate (USP);

65% malt extract (w / v);

2.5% propylene glycol (w / v);

0.1% sorbic acid (w / v);

purified water to equal 100%.

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Detailed description of the invention

The present invention relates to a aqueous pharmaceutical composition comprising:

(a) from 0.1% to 10% by weight of a compound of quinolone; wherein the quinolone compound is selected from orbifloxacin, grepafloxacin, nalidixic acid, sparfloxacin and trovafloxacin mesylate;

(b) from 0.2% to 20% by weight of a resin of cationic ion exchange prepared from a copolymer porous methacrylic acid crosslinked with divinylbenzene; Y

(c) pharmaceutically acceptable excipients to match 100%.

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The present invention further relates to a aqueous pharmaceutical composition consisting of

purified water at 33.75% (w / v);

2% orbifloxacin (w / v);

lactic acid at pH 4.5;

polystyrene ion exchange resin 12% (w / v) sodium sulfonate (USP);

65% malt extract (w / v);

2.5% propylene glycol (w / v);

0.1% sorbic acid (w / v);

purified water to equal 100%.

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Quinolones and derivatives thereof useful in the practice of present invention

Quinolones and derivatives thereof useful in the practice of the present invention include orbifloxacin, grepafloxacin, nalidixic acid, ofloxacin, sparfloxacin and trovafloxacin mesylate. The preferred quinolone is orbifloxacin, available from Schering Plow, Kenilworth, NJ as ORBAX®.

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The quinolone compounds useful in the practice of the present invention comprise from 0.1% to 10% by weight  of the pharmaceutical compositions of the present invention. Plus preferably, quinolone compounds useful in practice of the present invention comprise from about 0.5% to 5% by weight of the pharmaceutical compositions herein invention.

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Ionic exchange resins useful in the practice of present invention

The ion exchange resins useful in the practice of the present invention include cationic resins such as: AMBERLITE® IRP-64 (a porous copolymer of methacrylic acid crosslinked with divinylbenzene) and AMBERLITE® IRP-69 (USP sodium polystyrene sulfonate). The Preferred resin is AMBERLITE® IRP-64. Resins AMBERLITE® are available from the Rohm and Haas Company, Philadelphia, PA. The DOWEX® resins available from Dow Chemical Company, Midland, MI, are also useful in the practice of present invention These DOWEX® resins are exchangers strong cationics based on polystyrene sulfonic acid with a variable crosslinking (1-12% divinylbenzene) in A diversity of particle sizes.

In addition, said AMBERLITE® IRP 69 (polystyrene sodium sulphonate) is commercially available as sodium salt. However, it is within the scope of the present invention. convert sodium salt into other forms of salt that include, but They are not limited to, K and Li.

The ion exchange resins useful in the practice of the present invention comprise from 0.2% to 20% in weight of the pharmaceutical compositions of the present invention. More preferably, the ion exchange resins useful in the practice of the present invention comprise about 0.5% to 15% by weight of the pharmaceutical compositions of the present invention

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Pharmaceutically acceptable excipients useful in practice of the present invention

As indicated earlier in this document, pharmaceutically acceptable excipients include, but not limited to resins, fillers, binders, lubricants, solvents, emollients, disintegrants, cosolvents, surfactants, preservatives, sweetening agents, agents flavorings, buffer systems, pharmaceutical colors or pigments and viscosity agents.

The solvent is water.

The flavoring agents among those useful in This document includes those described in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, P. 1288-1300, incorporated as a reference in this document. Pharmaceutical compositions suitable for use in this document usually contain the 0-5% flavoring agents. The co-solvents Preferred include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycols. Pharmaceutical compositions of the present invention include 0.01% to 30% of co-solvents

Preferred buffer systems include, but not are limited to, NaOH, acetic, boric, carbonic, phosphoric acids, succinic, maleic, tartaric, citric, benzoic, lactic, glyceric, gluconic, glutaric and glutamic and its sodium salts, potassium and ammonium The pharmaceutical composition of the present invention generally contains from 0.1% to 20% of systems tampon.

Preferred surfactants include, but not are limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ether, sucrose monoesters and esters and lanolin ethers, alkyl sulfate salts, sodium salts, potassium and ammonium fatty acids.

Preferred preservatives include, but are not limit, phenol, alkyl esters of parahydroxybenzoic acid, sorbic acid and methylparaben acid o-phenylphenolbenzoic and salts thereof, chlorobutanol, benzyl alcohol, thimerosal, acetate and nitrate phenylmercuric, nitromersol, benzalkonium chloride, cetylpyridinium, methylparaben and propylparaben. It preferred particularly sorbic acid. The compositions of the present Invention generally include 0.01% to 5% preservatives.

Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, syrup malt extract, mannitol and aspartame. It is particularly preferred malt extract syrup. Sweeteners are generally used such as sucrose, glucose, saccharin and sorbitol at 0.1% levels at 10% Sweeteners such as syrup are generally used. malt extract at levels of 10% to 75%.

Preferred viscosity agents include, but not limited to, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, gum arabic, guar gum, Xanthan gum and tragacanth. They are particularly preferred methylcellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethyl cellulose, and aluminum and magnesium silicate. The compositions of the present invention include from 0.1% to 5% of viscosity agents.

The compositions of the present invention may optionally contain lactose, mannitol, sorbitol, phosphate of tribasic calcium, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextrocellulose and cellulose microcrystalline, magnesium stearate, stearic acid, talc, colloidal silicon dioxide, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, and microcrystalline cellulose, gum Arabic, tragacanth, hydroxypropyl cellulose, starch pregelatinized, gelatin, povidone, ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose

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Preparation of the compositions of the present invention

The compositions of the present invention are prepared according to methods known to specialists in The technique. Basically, the preparation procedure involves the dissolving quinolone in an aqueous medium followed by the addition of the ion exchange resin to form a complex drug / resin The complex can be suspended directly in suitable carriers with flavoring agents such as, but not are limited to, a syrup base (malt extract) with the help of a anti-caking agent such as, but not limited to, colloidal silicon and a preservative, such as, but not limited to, sorbic acid

The drug / resin complex can also be insulate and dry for later use. This would be advantageous when reconstitution is desired in the pharmacy or they are being used Very bitter drugs Specifically, the quinolone complex and ion exchange resin can be mixed with, for example, lactose, magnesium stearate, silicon dioxide, talc, cellulose microcrystalline or gelatin, to prepare a powder that can be send to the pharmacy and reconstitute in a dosage form Tasty oral liquid by the pharmacist. For drugs very bitter, the drug / resin complex can be isolated, for example, by rinsing with deionized water of the drug that is not forming complex (or free). The isolated and dry powder will contain substantially only drug / resin complex. This complex of drug / resin isolated (substantially devoid of drug free) more pure can be formulated in an oral liquid preparation It contains little or no amount of bitter free drug.

The following non-limiting Examples 1 and 2 illustrate the compositions of the present invention. Said Examples  they are prepared based on weight with respect to volume (w / v).

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Example one

Purified water, pure USP - 33.75%

Orbifloxacin - 2%

Lactic acid, USP at pH 4.5

Polystyrene ion exchange resin sodium sulphonate (USP) - 12%

Malt Extract - 65%

Propylene Glycol - 2.5%

Sorbic Acid - 0.1%

Purified water, pure USP to match the 100%

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The general procedure to prepare the Composition described in Example 1 is as follows:

1) Load orbifloxacin in water and mix well.

2) Add lactic acid and adjust the pH to 4,5.

3) Load sodium polystyrene sulfonate resin and mix well to form a paste.

4) Load malt extract syrup in the Pasta and mix well.

5) Dissolve sorbic acid in propylene glycol and load it into the paste formed in stages 3 and 4.

6) Add water to equal 100%, by weight Regarding volume.

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Example 2

Purified water, USP - 45%

Orbifloxacin - 3%

Lactic acid at pH 5.5

AMBERLITE IRP-64 - 15%

50% NaOH w / w at pH 5.5

Sorbic acid - 0.1%

Propylene Glycol - 10%

Colloidal Silicon Dioxide - 1.5%

Malt extract to match 100%

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The general procedure to prepare the Composition described in Example 2 is as follows:

1) Load orbifloxacin in water and mix well.

2) Add lactic acid and adjust the pH to 4,5.

3) Load Amberlite® IRP-64 and Mix well to form a paste.

4) Adjust the pH to 5.5 by adding 50% NaOH w / w.

5) Dissolve sorbic acid in propylene glycol and add it to the adjusted pH paste.

6) Add colloidal silicon dioxide and mix well.

7) Add malt extract syrup until equal 100%, by weight with respect to volume.

Claims (5)

1. An aqueous pharmaceutical composition that understands: (a) from 0.1% to 10% by weight of a compound of quinolone; wherein the quinolone compound is selected from orbifloxacin, grepafloxacin, nalidixic acid, sparfloxacin and trovafloxacin mesylate; (b) from 0.2% to 20% by weight of a resin of cationic ion exchange prepared from a copolymer porous methacrylic acid crosslinked with divinylbenzene; Y (c) pharmaceutically acceptable excipients to match 100%. 2. The composition according to the claim 1, wherein the quinolone is orbifloxacin. 3. The composition according to the claim 2, wherein (a) orbifloxacin is 0.5% to 5% in weigh; and (b) the cationic ion exchange resin is of 0.5% to 15% by weight. 4. The aqueous pharmaceutical composition according with claim 1, it consists of purified water at 45% (w / v); 3% orbifloxacin; lactic acid at pH 4.5; AMBERLITE IRP-64 at 15% (p / v); 50% NaOH (w / w) at pH 5.5; 0.1% sorbic acid (w / v); 10% propylene glycol (w / v); 1.5% colloidal silicon dioxide (w / v); malt extract to match 100%.

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5. An aqueous pharmaceutical composition that consists in purified water at 33.75% (w / v); 2% orbifloxacin (w / v); lactic acid at pH 4.5; polystyrene ion exchange resin 12% (w / v) sodium sulfonate (USP); 65% malt extract (w / v); 2.5% propylene glycol (w / v); 0.1% sorbic acid (w / v); purified water to equal 100%.